Preparation of nitrophenyloxazolines



United States Patent PREPARATION OF NITROPHENYLOXAZOLINES Basil JasonHeywood, Dagenham, England, assignor, by

mesne assignments, to Parke, Davis & Company, Detroit, Mich., acorporation of Michigan No Drawing. Application November 16, 1951 SerialNo. 256,821

Claims priority, application Great Britain November 22, 1950 Claims.(Cl. 260-307) This invention is for improvements in or relating to theproduction of oxazolines and is especially, though not exclusively,concerned with the preparation of the compound threo2-dichloromethyl-4-hydroxymethyl-5-p-nitrophenyl-A -oxazoline, the DLand D() forms of which possess therapeutic utility but which areprimarily useful as intermediates for the preparation of thecorresponding forms of threo 2-dichloracetamido-l-p-nitrophenylpropane1:3 diol, the D() form of which is the antibiotic known aschloramphenicol.

It is known that the threo forms of 2-amino-1-p-nitrophenylpropane1:3-diols and of corresponding 2-aeylamido compounds can be prepared bythe hydrolysis of threo 2-substituted-4-hydroxymethyl(or acyloxymethyl)-S-p-nitrophenyl-A -oxazolines. Convenient starting materials for thepreparation of these oxazolines are the corresponding erythro (otherwiseknown as allo) forms of 2-acylamido-l-p-nitrophenylpropane 1:3-diols andthe process then has involved at one stage or another the step ofepimerisation.

As a result of research in connection with the aforesaid process, thepresent applicants have now discovered that the desired threo oxazolinesof the general formula:

| Br I can readily be obtained, uncontaminated to any substantial extentwith erythro epimer, if the erythro 2-acylamido- 1-p-nitrophenylpropane1:3-diols are first converted into derivatives of the type:

ONO: NHC 0R1 In these formulae R represents an acyl or carboalkoxygroup, COR; represents an aliphatic acyl group containing not more than4 carbon atoms, preferably acetyl or halogen-substituted acetyl, and Rrepresents either a hydrogen atom or the group R.

The process of the present invention consists in reacting the nitricester of general Formula II with alkali (preferably sodium hydroxide),preferably in the cold or at moderate temperature (i. e. at atemperature not in excess of about 40 C.) and preferably in an organicsolvent such as aqueous ethyl alcohol.

When the radical R is a readily hydrolysable group such as acetyl,benzoyl, acid succinyl or carbethoxy, it will be hydrolysed under theconditions of reaction of the nitric ester of Formula II with alkali, inwhich event the product of the reaction is a 4-hydroxymethyl oxazoline.Where, however, a more stable group R is employed the reaction productis a 4-acyloxymethyl or 4-carboalkoxyoxymethyl oxazoline, the acyl orcarboalkoxy group of which is either removed during the subsequent stageof hydrolysis, in

known manner, of the oxazoline or subsequent thereto. It is, of course,possible to choose the COR, and R groups such that the conditions forhydrolysis of the R group will ensure hydrolysis also of the COR groupand, if such conditions are applied to hydrolysis of the oxazoline or tothe resultant product of hydrolysis, the ultimate product is the threo2-amino-l-p-nitrophenylpropane 1:3-diol instead of the corresponding2-acylamido compound.

Since an important feature of the present invention is to provide anoxazoline which is directly convertible by hydrolysis intochloramphenicol or the DL-mixture of which it is the D-compound, it ispreferred that the radical R shall be dichloromethyl and R be a readilyhydrolysable group, in which event the reaction may be representedschematically as follows:

ONO: NHC 0R1 OrN CHCHCHOR (erythro) lalkall mNQcH-pH-cmon C in (threo)According to a preferred feature of the invention,

DL- or L-erythro 2-dichloroacetamido-3-acetoxy-l-pnitrophenylpropanel-ol is treated with concentrated nitric acid, s. g. 1.50) and analcoholic solution or suspension of the resultant nitric ester istreated with a slight excess of sodium or potassium hydroxide solutionat room temperature or at a moderate temperature (i. e. a temperaturenot exceeding about 40 C.) to form DL- or D-threo 2- dichloromethyl 4hydroxymethyl 5 p nitrophenyl- A -oxazoline.

A particular advantage of the present invention is that the preferredoxazolines, namely DL and D() threo 2- dichloromethyl 4 hydroxymethyl 5p nitrophenyl- A -oxazolines can be obtained directly in a pure stateuncontaminated by any of the other isomeric Z-dichloromethyl 4 pnitrophenylhydroxymethyl A oxazolines and as such can be converted (bydissolving in dilute mineral acid followed by neutralisation with abase) into DL- or D-threo 2-dichloroacetamido-l-p-nitrophenylpropane 1:3diol. The full process can then be regarded as a process for theinversion of erythro Z-dichloroacetamidol-p-nitrophenylpropane 1:3-diols.

The present invention is illustrated by the following examples:

Example I DL erythro 2 dichloroacetamido 3 acetoxy l pnitrophenylpropane l-ol (1.0 g.) was added to stirred nitric acid (4.0cc.; s. g. 1.50), cooled to 60 C. The stirred pale yellow nitric acidsolution was allowed to warm spontaneously to 0 C. over about one hour.The solution was then poured into a stirred mixture of water (25 cc.)and ice (25 g.) and the suspension so obtained stirred for 15 minutes.The white solid was filtered off, powdered in a mortar, and washed withwater. The yield of crude nitric ester was almost quantitative.Crystallisation of the crude product from methanol (15 cc.) gave pureDL-erythro 2-dichloroacetamido-3-acetoxy-l-p-nitrophenylpropane l-olnitric ester in pale yellow cubes, M. P. 126-7 C. The yield was 0.80 g.or 71.5% of theory.

The DL-erythro 2-dichloroacetamido-3-acetoxy-l-p-nitrophenylpropane 1-01was obtained by reacting DL- erythro 2-dichloracetamido-1-p-nitrophenylpropane 1:3- diol with slightly overthe theoretical quantity of acetyl Chloride in the presence of pyridine.The product melts at 116-7 C.

The DL-erythro 2-dichloracetamido-3-acetoxy-l-p-nitrophenylpropane l-olnitric ester (410 mg), as prepared above, was suspended in methanol (8cc.) at C. To the stirred suspension was added slowly 2 N sodiumhydroxide solution (1 cc.). After three minutes a pale yellow solutionwas attained and the solution was then gradually heated to 30-40 C.After maintaining at this temperature for 10 minutes, the reactionmixture was cooled to 10 C. and neutrslised with 2 N acetic acidsolution. The product crystallised out. adding distilled water, as paleyellow plates. Crystallisation of the product from aqueous methanol gavepure DL-thrco 2-dichlorcmethyl-4-hydroxymethyl-S-p-nitrophenyl-u-oxazoline, M. P. 12S-9 C.

If the crude DL-erythro2-dichloracetamido-3-acetoxyl-p-nitrophenylpropane l-ol be converteddirectly to the oxazoline, the overall yield then is 80% of thetheoretical yield.

Example II L-erythro2-dichloroacetamido-3-acetoxy-l-p-nitrophenylpropane l-ol (1.35 g.) wasadded evenly to stirred nitric acid (s. g. 1.50) cooled to about 30 C.The reaction mixture was allowed to warm spontaneously to 0 C. and theclear colourless solution so obtained poured onto a stirred ice-watermixture g.). The white microcrystalline suspension was stirred for 10minutes prior to filtering off and water-washing the crude L-erythro2-dichloracetamido-3-acetoxy-1-p-nitrophenylpropane l-ol l-nitric ester.The yield of this material was 90% of theory (1.35 g.) and the meltingpoint of the material after crystallisation from methanol was 139-40 C.

Crude L-erythro Z-dichloracetamido-3-acetoxy-l-p-nitrophenylpropane 1-01ester (2.0 g.) was suspended in methanol (10 cc.) and then a slightexcess of 2 N sodium hydroxide added. At first a yellow solution wasobtained, but later crystals separated out. After standing at laboratorytemperature for three-quarters of an hour and then at 35 C. for 10minutes, the suspension was cooled to 5 C. prior to filtering ofi thepale yellow crystals. The D-threo2-dichloromethyl-4-hydroxymethyl-S-p-nitrophenyl-d -oxazoline (1.15 g.)was obtained in a 77.5% of theory yield and the product melted at l33-5C.

The overall yield for the two stages was 70% of theory.

Exrzmple III DL erythro2-dich1oroacetamido-3-benzoxy-l-p-nitrophenylpropane 1-ol (0.96 g.) wasadded evenly to stirred nitric acid (s. g. 1.50) at about 30 C. overfive minutes. During the course of one hour the pale yellow solution wasallowed to warm spontaneously to 0 C. The solution was poured onto astirred mixture of water cc.) and ice (25 cc.). After stirring for 15minutes, the white suspension was filtered and the solid washed wellwith water and dried in a vacuum desiccator. The yield (1.10 g.) was 95%since dinitration had occurred and the product was therefore, DL-erythro2-dichloracetamido-3-m-nitrobenzoxy-l-p-nitrophenylpropane l-ol l-nitricester. The melting point of the product after crystallisation frommethanol was 138.8 to 141.5 C.

DL-erthyro 2-dichloracetamido-3-rn-nitrobenzoxy-1-pnitrophenylpropanel-ol l-nitric ester (0.6 g.) was suspended in stirred methanol (12 cc.)at 0 C. and 2 N sodium hydroxide (1.5 cc.) was added to give a paleyellow solution. The reaction mixture was then heated to -40 C. and heldat this temperature for 10 minutes. The solution was cooled to 10 C.prior to precipitating out the oxazoline by the addition of distilledwater. The

yield of crystals (0.23 g.) was 64% of theory. The crude DL threo2-dichloromethyl-4-hydroxymethyl-5-pnitrophenyl-n -oxazoline melted at127-1285 C.

Example IV DL-erythro 2dichloracetamido-3-carbethoxyoxy-l-pnitrophenylpropane 1-01 (1.98 g.)was converted to the l-nitric ester in a similar way to that describedin the preceding examples. The yield of DL-erythro2-dichloracetamido-3-carbethoxyoxy-l-p-nitrophenylpropane 1 ol l-nitricester was 44% of theory (2.05 g.) and the melting point was l20-123.5 C.

The crude nitric ester obtained above was dissolved in methanol (20 cc.)at 0 C. and 2 N sodium hydroxide (5 c:.) added. The solution wasmaintained at 30-40 C. for 10 minutes and then cooled to 10 C. Theproduct crystallised out on addition of distilled water. The yield ofcrude DL-threo 2-dichloromethyl-4-hydroxymethyl-5- p-nitrophenyl-a-oxazoline was 60% of theory and it melted at 123.5-128 C.

Example V DL-erythro 2dichloracetamido-3-succinoxy-l-p-nitrophenylpropane l-ol (2 g.) wasconverted to the l-nitric ester in a similar way to that described inthe preceding examples. The crude nitric ester, which was not obtainedcrystalline, was converted directly to the oxazolinc by treatment of amcthanolic solution at 30-40 C. with 2 N sodium hydroxide which wasadded dropwise at such a rate that the reaction medium was always justalkaline to Clayton Yellow test paper. The reaction mixture wasmaintained for 10 minutes at 30-40 C. after the last addition of sodiumhydroxide and then cooled to 10 C. The oxazoline was isolated in thesame way as described in the preceding examples.

Example VI DL-erythro 2 dichloracetamido 3acetoxy-l-p-nitrophenylpropane l-ol nitric ester (410 mg. as prepared inExample I) was suspended in methanol (8.0 cc.) at 0 C. while 2 Npotassium hydroxide 1.5 cc.) was added gradually. The reaction mixturewas allowed to stand for one hour at 0 C. and then heated to 3040 C. for10 minutes. The product was isolated by first cooling the reactionmixture to 10 C. and then by adding distilled water. The DL-threo2-dichloromethyl-4-hydroxymethyl- S-p-nitrophenyl-A -oxazoline (210 mg.,M. P. 127-8 C.) was obtained in a 76% of theory yield.

I claim:

1. A process for the preparation of the threo forms of 2 dichloromethyl4 hydroxymethyl 5 p nitrophenyl-d -oxazoline which comprises treatingwith alkali metal hydroxide at a temperature below about 40 C. anerythro form of 2-dichloracetarnido-3-acetoxy-l-p-nitrophenylpropanel-ol nitric ester.

2. A process for the preparation of the threo forms of 2 dichloromethyl4 hydroxymethyl 5 p nitrophenyl-n -oxazoline which comprises treatingwith alkali metal hydroxide at a temperature below about 40 C. anerythro form of 2-dichloroacetamido-3-benzoxy-l-p-nitrophenylpropanel-ol nitric ester.

3. A process for the preparation of the threo forms of 2 dichloromethyl4 hydroxymethyl 5 p nitrophenyl-A -oxazoline which comprises treatingwith alkali metal hydroxide at a temperature below about 40 C. anerythro form of 2-dichloracetamido-3-carbethoxyoxy-1-pnitrophenylpropanel-ol nitric ester.

4. A process for the preparation of the threo forms of 2 dichloromethyl4 hydroxymethyl 5 p nitrophenyl-A -oxazoline which comprises treatingwith alkali metal hydroxide at a temperature below about 40 C. anerythro form of 2-dichloracetamido-3-succinoxy-l-p-nitrophenylpropanel-ol nitric ester.

5. Process for preparing an oxazoline having the ONO:

l NOr-O-CH-(fH-CEOR NHCOR:

where R is a member of the class consisting of carboxylic acid acyl andcarboalkoxy groups by reacting said substituted propane compound in anorganic solvent medium: with alkali metal hydroxide at a temperaturebelow about 40 C.

References Cited in the file of this patent UNITED STATES PATENTSMoersch et al. July 7, 1950 Moersch et a1 July 24, 1951

5. PROCESS FOR PREPARING AN OXAZOLINE HAVING THE FORMULA